Submissions for variant NM_002769.5(PRSS1):c.200+1G>A

dbSNP: rs143909348

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455871	SCV000540127	benign	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Does not pass quality filter; published as protective factor against pancreatitis
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463153	SCV000552152	uncertain significance	Hereditary pancreatitis	2023-08-25	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 403350). This variant has not been reported in the literature in individuals affected with PRSS1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects a donor splice site in intron 2 of the PRSS1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in PRSS1 cause disease.
Mendelics	RCV000463153	SCV001137529	benign	Hereditary pancreatitis	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000463153	SCV001174641	benign	Hereditary pancreatitis	2018-12-18	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000463153	SCV002049835	uncertain significance	Hereditary pancreatitis	2020-12-08	criteria provided, single submitter	clinical testing	The PRSS1 c.200+1G>A variant (rs143909348) has been reported in an individual with chronic alcohol intake, but no presentation of pancreatitis (Chen 2003). This variant is also reported in ClinVar (Variation ID: 403350), and is found in the general population with an overall allele frequency of 0.46% (1128/246316 alleles, including a single homozygote) in the Genome Aggregation Database, but is considered a low confidence variant in the database. This variant disrupts the canonical splice donor site of intron 2, which is likely to negatively impact gene function. However, the loss of PRSS1 activity has been suggested to be protective against pancreatitis, and is supported by the absence of any nonsense or canonical splice site variants associated with hereditary pancreatitis (Chen 2003). Furthermore, loss-of-function variants in SPINK1, which is a PRSS1 inhibitor, are causative of hereditary pancreatitis (Chen 2000). Although the PRSS1 c.200+1G>A variant is considered unlikely to be disease-causing for pancreatitis, it is unknown if the variant could be associated with other clinical symptoms. References: Chen J et al. Mutational analysis of the human pancreatic secretory trypsin inhibitor (PSTI) gene in hereditary and sporadic chronic pancreatitis. J Med Genet. 2000; 37(1):67-9. Chen J et al. "Loss of function" mutations in the cationic trypsinogen gene (PRSS1) may act as a protective factor against pancreatitis. Mol Genet Metab. 2003; 79(1):67-70.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000455871	SCV002511649	benign	not specified	2022-04-26	criteria provided, single submitter	clinical testing	Variant summary: PRSS1 c.200+1G>A alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. As the molecular disease mechanism for PRSS1 mediated Chronic Pancreatitis is gain of function, loss of function variants in PRSS1 are not consistent with the established mechanism. The variant allele was found at a frequency of 0.00026 in 226894 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 1.058 fold of the estimated maximal expected allele frequency for a pathogenic variant in PRSS1 causing Chronic Pancreatitis Risk phenotype (0.00025), strongly suggesting that the variant is benign. To our knowledge, no penetrant association of c.200+1G>A in individuals affected with Chronic Pancreatitis (CP) Risk and no experimental evidence demonstrating its impact on protein function have been reported. This variant is listed with a clinical significance of protective in one record of non-CP carriers reported in the "Genetic Risk Factors in Chronic Pancreatitis" database. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign, n=3; VUS, n=2). Based on the evidence outlined above, the variant was classified as benign.